Gamma-Aminobutyric acid (GABA) is an important inhibitory transmitter in the nervous systems of a variety of species. It is important in the regulation of neuronal excitability and in synaptic transmission. The applicant has developed a hypothesis that suggests the possibility that there may be a defect in the function of the GABA system in the brains of individuals who may have a predisposition to schizophrenia. We have begun the test of this hypothesis by studying the distribution and properties of the enzyme that forms GABA from glutamic acid in brain, L-glutamic decarboxylase (GAD), in the brains obtained at autopsy of 12 normal and 4 schizophrenic subjects. The current results indicate the possibility that there may be an abnormality in GAD distribution in some areas of the thalamus. We propose to study the GAD activities in different thalamic nuclei. In addition, new emphasis will be placed on areas of the limbic system, in which GAD activity is very high. These are the nucleus accumbens septi, nucleus centralis of the amygdala, anterior perforated substance, and nucleus of the diagonal band. Techniques for visualizing GAD, and possibly other enzymes, will be applied to autopsy samples of human brain (normal and schizophrenic) by immunocytochemical methods that have been newly developed in our laboratories. It would be of great importance from an experimental point of view, as well as in the development of therapies, to be able either to increase or decrease the effectiveness of this system. An increase might be helpful in epilepsy and Huntington's chorea, while a decrease might be of some therapeutic value in Parkinson's disease. There are five focal points at which it might reasonably be possible to influence the activity of the GABA system. These are the activity of GABA neurons themselves, and the synthesis of GABA, its release, postsynaptic effectiveness, and synaptic inactivation by carrier-mediated transport. A variety of approaches to influence the above processes by pharmacological and biochemical methods is outlined. BIBLIOGRAPHIC REFERENCE: I. Goetz, E. Roberts, and D.E. Comings. Fibroblasts in Huntington's Disease. New England J. of Med., 293: 1225-1227 (1975).